Project Summary/Abstract: Metastasis is the leading cause of death from cancer. Metastasis to bone represents a particularly poor prognosis. Unfortunately, the skeleton is one of the most common sites of metastasis for cancers such as breast, prostate and lung. Further, metastasis to bone results in significant pain, loss of mobility and increased fractures, among other comorbidities. The underlying mechanisms are incompletely understood and treatment options are mostly limited to attempting to reduce pain and fracture risk after diagnosis. Therefore, an enhanced understanding of the underlying etiology and/or a novel strategy to prevent or reduce bone metastasis would represent a significant advance to a field sorely in need of new options. One major obstacle to understanding, as well as developing therapeutic options for bone metastases is the paucity of pre-clinical models that faithfully recapitulate this multi-stage complex process. We have identified a novel genetically engineered mouse model in which to study lung cancer progression and metastasis to bone. Further, we believe we have identified a novel risk factor for cancer cell growth and survival as well as a factor that strongly influences the bone microenvironment in inorganic phosphate (Pi). Studies proposed herein will probe at the underlying mechanisms of bone metastasis combining a state-of-the-art mouse metastasis model, advanced microscopy and micro-computed tomography in the context of a novel and highly translational nutrition based prevention approach. Specifically, we will test the hypothesis that: The KrasG12D; Lkb1fl/fl; Rosa-luciferase mouse represents a model of spontaneous lung cancer metastasis to bone. Further, that this model can be used to study therapeutic and prevention modalities as well as provide mechanistic insight into this complex disease. To test this hypothesis we will: 1) therapeutically target spontaneous metastasis to bone using the KLLlenti mouse model, and 2) determine if differences in Pi transport drive a bone seeking phenotype. Impact: Results from the current proposal have the potential to provide new information about the mechanisms by which a common nutritional element might be manipulated to alter cell behavior related to cancer etiology as well as a better understanding of the skeletal environment which promotes tumor cell establishment.